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Histone variants are the paralogs of core histones (H2A, H2B, H3 and H4). They are stably expressed throughout the cell cycle in a replication-independent fashion and are capable of replacing canonical counterparts under different fundamental biological processes. Variants have been shown to take part in multiple processes, including DNA damage repair, transcriptional regulation and X chromosome inactivation, with some of them even specializing in lineage-specific roles like spermatogenesis. Several reports have recently identified some unprecedented variants from different histone families and exploited their prognostic value in distinct types of cancer. Among the four classes of canonical histones, the H2A family has the greatest number of variants known to date, followed by H2B, H3 and H4. In our prior review, we focused on summarizing all 19 mammalian histone H2A variants. Here in this review, we aim to complete the full summary of the roles of mammalian histone variants from the remaining histone H2B, H3, and H4 families, along with an overview of their roles in cancer biology and their prognostic value in a clinical context.

Chromatin remodeling factors efficiently and precisely establish, maintain, regulate, and distinguish between chromatin states in eukaryotes. DECREASE in DNA METHYLATION 1 (DDM1) is an important heterochromatin remodeling factor in plants that is responsible for maintaining heterochromatin DNA methylation and suppressing most transposable elements. Previous studies have predominantly focused on the effects of DDM1 on chromatin, with only a few focusing on its remodeling mechanisms. However, recent studies have greatly advanced understanding of the remodeling functions of DDM1 and, in particular, have clarified the mechanisms involved. In this review, we discuss the newly identified remodeling functions and mechanisms of DDM1. As DDM1 is closely involved in histone variant exchange, we first introduce the main histone variants associated with chromatin states in plants. Next, we focus on how DDM1 promotes the deposition of specific histone variants and describe its other remodeling functions. We propose that the core function of DDM1 is the regulation of histone variant distribution. DDM1 maintains heterochromatin by regulating the deposition of H2A and H3 variants, particularly by facilitating the exchange of specific histone variants.

Neurodevelopment is a highly regulated process that relies on the precise regulation of gene expression. Numerous epigenetic mechanisms contribute and cooperate to ensure the proper execution of developmental gene expression programs. Indeed, disruption of the molecular machinery regulating the deposition or removal of epigenetics markers is associated with numerous neurodevelopmental disorders, including autism spectrum disorder and intellectual disabilities. Among the various epigenetic marks that are fundamental for brain development, research has recently begun to focus on the role of histone variants and their associated chaperone proteins. Replication-independent histone variants can replace replication-dependent canonical histones in neuronal chromatin, giving nucleosomes unique properties that allow them to influence transcription. The deposition and removal of histone variants into neuronal chromatin are controlled by chaperone proteins that are integrated into chromatin remodelling complexes. Several studies report that the deposition and removal of histone variants by chaperone proteins from genes during development is pivotal for the regulation of gene expression, suggesting they are fundamental for neurodevelopment. This review will focus on the histone variants H2A.Z and H3.3, and the exclusive chaperones that regulate their dynamics, in gene expression during neurodevelopment and the progression of neurodevelopmental disorders.

Background Obesity has tremendous impact on the health systems. Its epigenetic bases are unclear. MacroH2A1 is a variant of histone H2A, present in two alternatively exon-spliced isoforms macroH2A1.1 and macroH2A1.2, regulating cell plasticity and proliferation, during pluripotency and tumorigenesis. Their role in adipose tissue plasticity is unknown. Results Here, we show evidence that macroH2A1.1 protein levels in the visceral adipose tissue of obese humans positively correlate with BMI, while macroH2A1.2 is nearly absent. We thus introduced a constitutive GFP-tagged transgene for macroH2A1.2 in mice, and we characterized their metabolic health upon being fed a standard chow diet or a high fat diet. Despite unchanged food intake, these mice exhibit lower adipose mass and improved glucose metabolism both under a chow and an obesogenic diet. In the latter regimen, transgenic mice display smaller pancreatic islets and significantly less inflammation. MacroH2A1.2 overexpression in the mouse adipose tissue induced dramatic changes in the transcript levels of key adipogenic genes; genomic analyses comparing pre-adipocytes to mature adipocytes uncovered only minor changes in macroH2A1.2 genomic distribution upon adipogenic differentiation and suggested differential cooperation with transcription factors. MacroH2A1.2 overexpression markedly inhibited adipogenesis, while overexpression of macroH2A1.1 had opposite effects. Conclusions MacroH2A1.2 is an unprecedented chromatin component powerfully promoting metabolic health by modulating anti-adipogenic transcriptional networks in the differentiating adipose tissue. Strategies aiming at enhancing macroH2A1.2 expression might counteract excessive adiposity in humans.

Background H2A.B, the most divergent histone variant of H2A, can significantly modulate nucleosome and chromatin structures. However, the related structural details and the underlying mechanism remain elusive to date. In this work, we built atomic models of the H2A.B-containing nucleosome core particle (NCP), chromatosome, and chromatin fiber. Multiscale modeling including all-atom molecular dynamics and coarse-grained simulations were then carried out for these systems. Results It is found that sequence differences at the C-terminal tail, the docking domain, and the L2 loop, between H2A.B and H2A are directly responsible for the DNA unwrapping in the H2A.B NCP, whereas the N-terminus of H2A.B may somewhat compensate for the aforementioned unwrapping effect. The assembly of the H2A.B NCP is more difficult than that of the H2A NCP. H2A.B may also modulate the interactions of H1 with both the NCP and the linker DNA and could further affect the higher-order structure of the chromatin fiber. Conclusions The results agree with the experimental results and may shed new light on the biological function of H2A.B. Multiscale modeling may be a valuable tool for investigating structure and dynamics of the nucleosome and the chromatin induced by various histone variants.

Histones are nuclear proteins essential for packaging genomic DNA and epigenetic gene regulation. Paralogs that can substitute core histones (H2A, H2B, H3, and H4), named histone variants, are constitutively expressed in a replication-independent manner throughout the cell cycle. With specific chaperones, they can be incorporated to chromatin to modify nucleosome stability by modulating interactions with nucleosomal DNA. This allows the regulation of essential fundamental cellular processes for instance, DNA damage repair, chromosomal segregation, and transcriptional regulation. Among all the histone families, histone H2A family has the largest number of histone variants reported to date. Each H2A variant has multiple functions apart from their primary role and some, even be further specialized to perform additional tasks in distinct lineages, such as testis specific shortH2A (sH2A). In the past decades, the discoveries of genetic alterations and mutations in genes encoding H2A variants in cancer had revealed variants’ potentiality in driving carcinogenesis. In addition, there is growing evidence that H2A variants may act as novel prognostic indicators or biomarkers for both early cancer detection and therapeutic treatments. Nevertheless, no studies have ever concluded all identified variants in a single report. Here, in this review, we summarize the respective functions for all the 19 mammalian H2A variants and their roles in cancer biology whilst potentiality being used in clinical setting.

To ensure proper chromosome segregation during cell division, the centromere in many organisms is transcribed to produce a low level of long non-coding RNA to regulate the activity of the kinetochore. In the budding yeast point centromere, our recent work has shown that the level of centromeric RNAs (cenRNAs) is tightly regulated and repressed by the kinetochore protein Cbf1 and histone H2A variant H2A.Z Htz1 , and de-repressed during S phase of the cell cycle. Too little or too much cenRNAs will disrupt centromere activity. Here, we discuss the current advance in the understanding of the action and regulation of cenRNAs at the point centromere of Saccharomyces cerevisiae . We further show that budding yeast cenRNAs are cryptic unstable transcripts (CUTs) that can be degraded by the nuclear RNA decay pathway. CenRNA provides an example that even CUTs, when present at the right time with the right level, can serve important cellular functions.

Aging is the progressive decline or loss of function at the cellular, tissue, and organismal levels that ultimately leads to death. A number of external and internal factors, including diet, exercise, metabolic dysfunction, genome instability, and epigenetic imbalance, affect the lifespan of an organism. These aging factors regulate transcriptome changes related to the aging process through chromatin remodeling. Many epigenetic regulators, such as histone modification, histone variants, and ATP-dependent chromatin remodeling factors, play roles in chromatin reorganization. The key to understanding the role of gene regulatory networks in aging lies in characterizing the epigenetic regulators responsible for reorganizing and potentiating particular chromatin structures. This review covers epigenetic studies on aging, discusses the impact of epigenetic modifications on gene expression, and provides future directions in this area.

Plants have developed multiple mechanisms as an adaptive response to abiotic stresses, such as salinity, drought, heat, cold, and oxidative stress. Understanding these regulatory networks is critical for coping with the negative impact of abiotic stress on crop productivity worldwide and, eventually, for the rational design of strategies to improve plant performance. Plant alterations upon stress are driven by changes in transcriptional regulation, which rely on locus-specific changes in chromatin accessibility. This process encompasses post-translational modifications of histone proteins that alter the DNA-histones binding, the exchange of canonical histones by variants that modify chromatin conformation, and DNA methylation, which has an implication in the silencing and activation of hypervariable genes. Here, we review the current understanding of the role of the major epigenetic modifications during the abiotic stress response and discuss the intricate relationship among them.

Active DNA demethylation is critical for controlling the DNA methylomes in plants and mammals. However, little is known about how DNA demethylases are recruited to target loci, and the involvement of chromatin marks in this process. Here, we identify 2 components of the SWR1 chromatin-remodeling complex, PIE1 and ARP6, as required for ROS1-mediated DNA demethylation, and discover 2 SWR1-associated bromodomain-containing proteins, AtMBD9 and nuclear protein X1 (NPX1). AtMBD9 and NPX1 recognize histone acetylation marks established by increased DNA methylation 1 (IDM1), a known regulator of DNA demethylation, redundantly facilitating H2A.Z deposition at IDM1 target loci. We show that at some genomic regions, H2A.Z and DNA methylation marks coexist, and H2A.Z physically interacts with ROS1 to regulate DNA demethylation and antisilencing. Our results unveil a mechanism through which DNA demethylases can be recruited to specific target loci exhibiting particular histone marks, providing a conceptual framework to understand how chromatin marks regulate DNA demethylation.